For more than two decades the delivery of bioactive agents from polymeric materials has attracted considerable attention of investigators working in the field of drug delivery systems. New technological advances have brought many innovative drug delivery systems to the market and others are close to commercialization. Polymers play an important role in the formulation of drug products. Polymer based excipients have been used in formulations for a variety of reasons, including taste masking, protection and stabilization of the drug, etc. The synthetic and naturally occurring polymers are being used in the form of matrix, hydrogels, microparticles, nanoparticles, films and sponges in the drug delivery system. The applications of polymers either synthetic or natural are continuing and increasing in the field of formulations of drugs. Many of the polymers are used in the oral delivery of the drugs either for film coating of the tablets or for the modified release of the drugs from the delivery systems. The choice of polymers for the investigators working in the field of the advanced drug delivery systems are severely limited by the candidate polymeric materials as evidenced by the relatively small number of polymeric materials available commercially in comparison to the number of drugs marketed.
Some of the synthetic polymers commercially available include cellulose derivatives like ethyl cellulose, cellulose acetate, cellulose acetate phthalate and acrylic acid and methacrylic acid polymers like Carbopol and Eudragit. The barrier coating of bitter drug with the various polymers is extensively used for taste masking of the drugs especially when the formulation is to be administered in the form of a liquid oral like the suspension or dry syrup. Taste masking is very important when the drug is extremely bitter. Perception of bitter taste makes the preparation unacceptable or unpalatable. Bitter taste of drugs that are orally administered is disadvantageous in several aspects. Taste is an important parameter governing compliance. The disagreeable taste of drugs causes difficulties in swallowing or causes patients to avoid their medication thereby resulting in low compliance of patients. Conventional taste masking techniques such as use of sweeteners, amino acids, flavoring agents are often inadequate in masking taste of highly bitter drugs like quinine, barberin, celecoxib, etoricoxib, antibiotics like levofloxacin, ofloxacin, sparfloxacin, ciprofloxacin, cefuroxime axetil, erythromycin and clarithromycin. Thus taste-masking technologies are considered important and developed by many researchers.
Japanese Patent Application JP 2003231647 A2 discloses an oral liquid preparation comprising fruit type flavors and sweeteners like acesulfame to mask the unpleasant taste or odor of pharmaceutical and food components. Japanese Patent Application JP 2001106641 discloses a chewable tablet wherein the bitter taste of the active ingredient is masked by the addition of the sugar alcohol like xylitol, a coolant like menthol and hard fat.
Although sweeteners and flavors were used for taste masking, this alone was not sufficient for taste masking of highly bitter drugs and use of polymeric materials was mostly favored and many efforts have been made to taste mask drugs using polymeric materials.
U.S. Pat. No. 6,514,492 discloses a liquid oral formulation of quinolones comprising ion exchange resins, such as methacrylic acid polymer crosslinked with divinylbenzene, for elimination of extreme bitterness of the quinolones. Patent Application WO 03/06066 A1 discloses ternary ionic complexes which have a pleasant taste. The complexes are used for liquid suspension dosage forms for the children. A complex is formed using an active ingredient with an ionisable cationic group and a charged polymer with an anionic group and a polymer with cationic charge.
A fast dissolving orally consumable film comprising a film forming polymer and ion exchange resin is disclosed in Patent Application WO 01/70194. The taste masking is achieved by the use of sulfonated polymer ion exchange resin comprising polystyrene cross-linked with divinylbenzene, such as Amberlite™. The taste masked antitussive film of dextromethorphan using amberlite and film forming polymers like xanthan gum, locust bean gum, carrageenan and pullulan is disclosed.
Patent Application WO 02/72111 discloses a taste masked pharmaceutical suspension comprising the antibiotic telithromycin which is coated by a waxy material like glyceryl monostearate and optionally by a binding agent or a polymer like Eudragit E. Granules and granules coated with a masked taste are disclosed in the patent application WO 02/72072. A bitter active ingredient like clarithromycin, coated by a waxy compound like gelucire and a polymer like eudragit E is disclosed. Japanese Patent Application JP 2001-172201 discloses a taste masking coating composition comprising polyvinyl acetate, hydrophilic additives and other conventional coating agents like kollidion and propylene glycol. Coated ibuprofen is compressed into chewable tablets.
Patent Application WO 00/18372 discloses grains obtained by spray solidification of drug, clarithromycin, glycerine fatty acid ester and an enteric or gastric polymer. The gastric polymer used for the taste masking was Eudragit E. A taste masked pharmaceutical composition containing acrylic polymeric coatings is disclosed in Patent Application WO 0269939.The microcapsules of the drug levofloxacin, were coated by the water-insoluble enteric coating, comprising methacrylic acid-Et acrylate copolymer, are disclosed.
Patent Application WO 01/80829 discloses the taste masking coating compositions containing polymers comprising polyvinyl acetate, and a dimethylaminoethyl methacrylate and neutral methacrylic acid ester. In addition to the polymers an alkali modifier may be added to the coating composition to enhance the release of the active agent. The coated granules are compressed into tablets. Patent Application WO 01/80826 discloses a coating composition based on the methacrylate polymer and the cellulose ester, which masks the undesirable taste of the pharmaceutically active agent like acetaminophen. The coating composition comprises dimethylaminoethyl methacrylate and neutral methacrylic acid ester polymer (Eudragit E 100), and a cellulose ester polymer (cellulose acetate).
The taste-masked pharmaceutical composition containing histamine H2 antagonist in the form of chewable tablets is disclosed in U.S. Pat. No. 6,270,807. The histamine H2 antagonist, famotidine was coated by a composition comprising water-insoluble component glyceryl monostearate and water-permeable methacrylate ester copolymer Eudragit NE30D to provide a taste-masking effect for a relatively short period when the compound is being chewed by a patient.
Patent Application WO 01/35930 discloses taste masked oral compositions based on polyacrylates. The effective taste masking of the active pharmaceutical like ciprofloxacin by granulation with aqueous solution of neutral methacrylic acid ester is disclosed. Patent Application WO 01/03698 discloses polymer blends for taste masking of the pharmaceutical liquid formulations. The pharmaceutically active drugs like antibiotics, analgesics, anti-inflammatory drugs, gastrointestinal drugs, antihistamines, decongestants, antidepressants, antipsychotics, antivirals, oncolytics, vaccines, antiepileptics, antiasthma drugs, and antispasmodics, are coated with effective amount of a polymer blend of (a) dimethylaminoethyl methacrylate and neutral methacrylic acid ester (MM/MAE) like Eudragit E and (b) a cellulose ester like cellulose acetate in an aqueous vehicle. The polymer coating masks the taste of the composition comprising levofloxacin.
Taste masking, rapid release coating systems are disclosed in the patent application WO 00/30617. The drug core of dextromethorphan is encased in the spacing layer comprising of ethyl cellulose and polyvinyl pyrrolidone and a taste masking layer comprising of Eudragit E. The resulting beads are taste less for approximately 30 seconds. European Patent EP 1279402 A1 discloses orodispersible tablets comprising of the allyamine or benzylamine or the salts e.g. terbinafine hydrochloride in the form of coated granules where the granules are coated by cellulose derivatives like hydroxypropyl methylcellulose, povidones, polyvinyl alcohols and further by ethyl cellulose and acrylic polymers. US Patent Application 2002-132006 A1 discloses an odor and taste masking coating comprising of hydroxyalkyl cellulose, an antitackiness agent and a methacrylate copolymer.
Patent Application WO 03/00225 A2 discloses a suspension formulation, which comprises of the taste masked powder of the active ingredient comprising a cellulose polymer and a methacrylic polymer along with alkaline agent and a adsorbing agent. US Patent Application 2002-197317 A1 discloses a coating composition containing polymer comprising dimethylaminoethyl methacrylate and neutral methacrylic acid ester, a cellulose ester polymer, and an alkaline modifier, which masks taste of the active ingredient.
A taste masked pharmaceutical particles containing a polymeric coating is disclosed in Patent Application EP 1166777. Taste masked particles are further formulated into chewable tablets. The core containing the active agent ibuprofen is coated by a enteric polymer and film forming polymer e.g. hydroxypropyl methyl cellulose phthalate and cellulose actetate. Coated particles are blended with other agents such as sweeteners like acesulfame, aspartame, citric acid, mannitol and flavoring agent and then compressed into chewable tablets. Patent Application WO 02/87622 A1 discloses an oral film preparation comprising a drug containing layer and two water swelling gel forming layers. Polymers such as polyacrylic acid and hydroxypropyl cellulose are used in the formulation. Texture masked particles coated by the film-forming polymer and anti grit agent are disclosed in Patent Application EP 1219291.Texture masked particles are formulated into the chewable tablets. The texture masking effect is achieved by coating the core comprising of acetaminophen and ethyl cellulose with hydroxypropyl methylcellulose. Japanese Patent Application JP 2002-292344 discloses film coating agents, which have higher taste masking effect and exhibit desirable drug release. The film coating agents comprise a dispersion of Eudragit NE 30 D (Ethyl acrylate-methyl methacrylate copolymer) and methylcellulose.
Patent Application JP 2000128776 discloses film coated pharmaceutical granules wherein the film coating comprises of aqueous dispersion of ethyl cellulose, Aquacoat ECD 30 and Eudragit NE 30 D (ethyl acrylate-methyl methacrylate copolymer emulsion.) The drug is released in 5, 10, and 20 min from the composition.
Taste masked pharmaceutical particles containing the polymeric coating are disclosed in Patent Application EP 1166777. The drug particles are taste masked using the polymeric coating which comprises a mixture of enteric polymer hydroxypropyl methyl cellulose phthalate and an insoluble film forming polymer, cellulose acetate. Patent Application JP 2000-053563 discloses the taste masked granular composition comprising the coating layer of ethyl cellulose to mask the bitter taste. Use of gastric soluble polymers for unpleasant taste masking is disclosed in JP 11228393. The polymers used for the coating comprise polyvinyl acetal diethylaminoacetate.
Use of cationic polymers comprising dimethylaminoethyl methacrylate and neutral methacrylic acid esters marketed as Eudragit E is disclosed in Patent Application WO 99/17742. U.S. Pat. No. 5,837,277 discloses a palatable pharmaceutical composition containing acrylic polymers. Acrylic polymers are used to taste mask the anti-inflammatory drug. Acrylic polymers used comprise copolymers of poly (Ethyl acrylate, Methyl methacrylate) in which quaternary ammonium groups have been introduced to modify the permeability of the ester marketed under the name Eudragit RL 30D and Eudragit RS 30D.
The following patents and patent applications disclose the use of polymers for the taste masking application of the drugs:    WO 00/06122 A1; JP 2000-007557 A2; JP 2000-007556 A2; EP 943341; WO 98/47493; WO 98/30209; WO 98/14179; WO 97/41839; WO 97/09967; WO 96/34628; EP 724880; WO 96/10993; EP 706821; WO 95/15155; JP 07076517; WO 95/05166; WO 94/27596; WO 94/12157; WO 94/05260; WO 93/24109; JP 05255075; WO 93/17667; JP 91-298966; JP 05201855; EP 523847
Patent Application WO 00/56266 discloses the use of a high viscosity swellable polymer carbomer, in combination with film forming polymethacrylates and channelising agents for taste masking of bitter drugs. The addition of the water swellable polymer aids in the fast release of the active ingredient in the gastric media. Patent Application WO 00/76479 discloses a taste masking composition, using a combination of two enteric polymers comprising methacrylic acid copolymer and a phthalate polymer. This application discloses the use of channelising agents, which comprise water soluble or water swellable materials to aid release of active ingredient. The enteric polymers as disclosed in the patent are known to release the active ingredient at alkaline pH where the polymers are soluble. The release of the active ingredient will be delayed due to the use of the enteric polymers and in case of the medicaments having a narrow absorption window limited to upper gastrointestinal tract; such system would be of limited use.
Microencapsulation of highly bitter drug cefuroxime axetil for taste masking is disclosed by M.Cuna et.al (M. Cuna, M. L. Lorenzo, J. L. Vila Jato, D. Torres, M. J. Alonso, Acta Technologiae et Legis Medicamenti. volume VII, N.3, 1996) using different polymeric materials like cellulose acetate trimellitate, HPMCP-50, HPMCP-55 with the final aim to mask the taste and assuring its release in the intestinal cavity. Alonso et al (M. J. Alonso, M. L Lorenzo-Lamosa, M.Cuna, J. L. Vila-Jato and D. Torres, Journal of Microencapsulation, 1997, Volume 14, No.5, 607-616) describe the encapsulation of cefuroxime axetil, a highly bitter drug, in pH sensitive acrylic microspheres in order to formulate a suspension dosage form. The acrylic polymers used were eudragit E, eudragit RL 100, eudragit L100-55. The cationic Polymer eudragit E showed a negative interaction with cefuroxime axetil. The enteric polymer eudragit L100-55 showed a favorable release in alkaline pH.
In the above disclosures the release of cefuroxime axetil was studied in the basic media whereas Dantzig et al (Anne H. Dantzig, Dale C. Duckworth, Linda B. Tabas, Biochimica et Biophysica Acta 1191, 1994, 7-13) showed that cefuroxime axetil is hydrolyzed to cefuroxime in the intestinal lumen by the esterases, reducing cefuroxime axetil concentration in the lumen and resulting in reduced absorption, resulting in lower bioavailability of Cefuroxime axetil in humans. Cefuroxime axetil already has a low bioavailability of 32-50% and hence a further reduction in the bioavailability due to the formulation aspects should be minimized. The optimum conditions for the spray congealing of the bitter drug clarithromycin using the mixture of the wax: glyceryl monostearate and a polymer: aminoalkyl methacrylate copolymer E (AMCE). (Yajima, Toshio; Umeki, Nobuo; Itai, Shigeru. Chemical & Pharmaceutical Bulletin (1999), 47(2), 220-225) are discussed
It is evident from the above disclosures, that taste masking can be achieved by various methods. Many natural and synthetic polymers, resins and waxes alone or in combination have been employed for taste masking. The enteric polymers like eudragit L are used for taste masking but the pH of saliva is near 5.8 and these polymers solubilize at pH beyond 5.5 so there is a possibility of drug being partially leached. Therefore there is a need for the development of taste masking polymer such that the bitter taste is completely masked by the polymer at the pH of saliva in mouth and in the reconstitution medium as in case of the liquid orals and further which is able to protect the drug in a biologically active form, from the moisture in the dosage form and releasing the drug rapidly in the stomach without affecting its absorption and bioavailability.
Most of the references described above, describe compositions, which satisfactorily mask the bitter taste of the medicament in the pharmaceutical compositions but cannot release the drug in gastric cavity immediately after ingestion without affecting the bioavailability. Further the polymers like ethyl cellulose, eudragit RS and RL would take some time to release the drug and enteric polymers like cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, eudragits like L 100 would delay the release of the drug till it reaches the small intestine. Hence such polymers might not be of use when the drug has to be absorbed immediately without, any delay or has an absorption window restricted to the upper gastric region. Thus there is a need to develop a polymer, which is effective in taste masking of the drug but does not cause a delay in the release of the drug.
Whilst the use of polymer coating as mentioned in the above examples may be effective for retarding dissolution of the drug during the time in contact with saliva, during the process of swallowing, it has disadvantages in preparing taste masked liquid formulations intended for long term storage in contact with liquid medium.
A large number of polymers, which exhibit pH dependant dissolution behavior, have been reported in literature. Polymers containing carboxylic functional groups as well as cellulose derivatives are known to dissolve at pH above 5.5. However, these polymers are not useful for taste masking, as they would dissolve at pH of saliva and at pH of reconstitution medium. Further these polymers will not release the encapsulated drug in the stomach since these polymers do not dissolve or swell sufficiently at pH prevalent in the stomach.
Polymers containing basic functional groups such as amino groups are known to dissolve at pH prevalent in the stomach. Such polymers are referred to as reverse enteric coatings. The polymer eudragit E marketed by Rohm and Haas belongs to this category. (Eudragit E, Technical literature Rohm and Haas). These polymers also show swelling at pH 5 and hence will release the drug at the pH of the saliva as well as the reconstitution medium and will not be useful for taste masking. There is therefore a need for the developing pH sensitive polymer compositions, which will exhibit very specific pH dependant behavior. The polymeric compositions disclosed in this invention exhibit specific pH dependent dissolution behavior and are not reported in the literature in the past.
Regardless of the numerous techniques and pharmaceutical adjuncts known in the art to mask the taste of bitter-tasting medicaments, there remains the need to find an effective technique, adjunct or combination thereof for specific agents.